Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and human: i.e., PPARxcex1, PPARxcex2 and PPARxcex4. The PPARs are believed to play a role in the regulation of lipid metabolism. They can be activated by high concentration of fatty acids and have been shown to regulate the expression levels of fatty acid binding proteins or enzymes involved in fatty acid oxidation.
It has previously been discovered that a certain class of thiazolidinediones are selective PPARxcex3 agonists (see, Willson et. al., J. Med. Chem. (1996) 39:665-668). Thiazolidinediones are a class of oral insulin-sensitizing agents that improve glucose utilization without stimulating insulin release. For instance, U.S. Pat. No. 4,287,200, discloses certain thiazolidine derivatives having the ability to lower blood glucose levels. In addition, U.S. Pat. No. 4,572,912, discloses thiazolindinedione derivatives having the ability to lower blood lipid and blood glucose levels. These compounds were shown to have the ability to decrease the levels of blood lipid peroxides, blood triglycerides and blood cholesterol.
Moreover, U.S. Pat. No. 5,338,855, discloses thiazolidine derivatives containing a quinone moiety. These compounds were shown to have the ability to reduce insulin resistance in the peripheral tissues and possess the ability to suppress hepatic gluconeogenesis in the liver.
In addition to being anti-diabetic agents which can lower the concentration of glucose and lipids in the blood, U.S. Pat. No. 5,594,015 discloses thiazolidine derivatives as being effective in the treatment of hyperproliferation of epithelial cell conditions, such as psoriatic activity.
The anti-diabetic effect of the thiazolidinediones and their PPARxcex3 agonist activity has implicated PPARxcex3 as the molecular target for the anti-diabetic effects of thiazolidinediones. PPARxcex3 is predominately expressed in adipose tissue and has been implicated as a master regulator of adipocyte differentiation in pre-adipose cell lines.
In view of the role PPARxcex3 plays in regulation of lipid and glucose metabolism and the agonistic behavior of thiazolidinediones, there remains a need in the art for new thiazolindinedione derivatives and more effective therapies for diabetes and other ailments. The present invention fulfills these and other needs.
This invention provides new thiazolindinedione derivatives. As such, in one aspect, the present invention provides compounds of Formula I: 
In Formula I, R1 and R2 are each independently a functional group including, but not limited to, hydrogen, C(O)xe2x80x94R6 and C(S)xe2x80x94R6. R6, in Formula I, is a functional group including, but not limited to, hydrogen, (C1-C12)alkyl, aryl, arylalkyl, (C1-C12)carboxyl, (C1-C12)NHR7, (C1-C12)NR7R8, OR7, NHR7, SR7, NR7 R8. R7, and R8, in Formula I, are each independently functional groups including, but not limited to, hydrogen, (C1-C12)alkyl, aryl and arylalkyl. The bond bisecting the functional group containing two sulfurs, indicates that the bond can be attached at anyone of the 3 carbon atoms between the two sulfur atoms.
In an alternative embodiment, R1 and R2 together with the sulfurs to which they are bound join to form a 1,2-dithiolane ring. In this embodiment, the 1,2-dithiolane ring can be substituted at the 3-position or the 4-position.
X, in Formula I, is a functional group including, but not limited to O, NR, C(O)O, OC(O)O and C(O)NR, wherein R is a functional group including, but not limited to, hydrogen and optionally substituted (C1-C6)alkyl. Y, in Formula I, is a functional group including, but not limited to, O, S and NR6, wherein R6 is a functional group including, but not limited to, hydrogen and optionally substituted (C1-C6)alkyl. In Formula I, the index xe2x80x9cnxe2x80x9d is an integer from 2 to 14; the index xe2x80x9cmxe2x80x9d is an integer from 0 to 14; the index xe2x80x9cqxe2x80x9d is an integer from 0 to 1; and the index xe2x80x9ctxe2x80x9d is an integer from 0 to 1, provided when m is 0 then q is 0, or a pharmaceutical acceptable salt or solvate thereof. Suitable salts include, but are not limited to, sodium, potassium and ammonium.
In another embodiment, the present invention provides a compound of Formula II: 
In Formula II, R1 and R2 are each independently a functional group including, but not limited to, hydrogen, C(O)xe2x80x94R6 and C(S)xe2x80x94R6. R6, in Formula II, is a functional group including, but not limited to, hydrogen, (C1-C12)alkyl, aryl, arylalkyl, (C1-C12)carboxyl, (C1-C12)NHR7, (C1-C12)NR7R8, OR7, NHR7, SR7, NR7R8. R7 and R8, in Formula II, are each independently a functional group including, but not limited to, hydrogen, (C1-C12)alkyl, aryl and arylalkyl. The bond bisecting the functional group containing two sulfurs, indicates that the bond can be attached at any of the 3 carbon atoms between the two sulfur atoms.
In an alternative embodiment, R1 and R2 together with the sulfurs to which they are bound join to form a 1,2-dithiolane ring. The 1,2dithiolane ring can be substituted at the 3-position or at the 4-position.
X, in Formula II, is functional group including, but not limited to O, NR, C(O)O, OC(O)O and C(O)NR, wherein R is a functional group including, but not limited to, hydrogen, optionally substituted (C1-C6)alkyl and optionally substituted aryl. Y, in Formula II, is a functional group including, but not limited to, O, S and NR6, wherein R6 is a functional group including, but not limited to, hydrogen and optionally substituted (C1-C6)alkyl. R4, in Formula II, is a functional group including, but not limited to, hydrogen, halogen, optionally substituted (C1-C6)alkyl and optionally substituted (C1-C6)alkoxy. R5, in Formula II, is a functional group including, but not limited to, hydrogen and optionally substituted (C1-C6)alkyl. In Formula II, the index xe2x80x9cnxe2x80x9d is an integer from 2 to 14; the index xe2x80x9cmxe2x80x9d is an integer from 0 to 14; and the index xe2x80x9cqxe2x80x9d is an integer from 0 to 1, provided when m is 0 then q is 0, or a pharmaceutical acceptable salt or solvate thereof. Suitable salts include, but are not limited to, sodium, potassium and ammonium.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the Formula I wherein R, R1, R2 X, Y, R3, R6, R7, R8, n, m, q and t have the same meaning as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical acceptable carrier.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the Formula II wherein R, R1, R2 X Y, R3, R4, R5, R6, R7, R8, n, m, and q have the same meaning as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical acceptable carrier.
In yet another aspect, the present invention relates to a method of treating a PPARxcex3 mediated disease or oxidative stress, comprising administering a therapeutically effective amount of a compound of Formulae I, II or mixtures thereof, to an individual suffering from a PPARxcex3 mediated disease. In other aspects, this invention provides methods for synthesizing the compounds of Formulae I and II.